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Blood Bros. is a wild west themed shooter, similar to Cabal. Up to two players control either a cowboy or a native American, shooting their way through the fictional Dodge City.

Enemies come in the form of cowboys and native Americans, either on foot or on horseback. Players can also destroy large parts of the background; barrels, glass bottles, stalagmites, bridges, tipi's and even entire buildings or mountains can be leveled. When the enemy gauge at the bottom of the screen is empty the level is completed and any remaining buildings will collapse by themselves. A chirpy and up-beat jingle is played and the players dance comically into the distance.

The gameplay is broken up in 5 level with 4 screens each. At the end of each level players must fight an end boss. The end bosses in order are a steam locomotive, a blimp, phoenix birds, a giant snake and finally Big Bad John.

Players have unlimited ammo but a limited amount of dynamite. Dynamite can be replenished by shooting incoming grenades, certain figures in the background or the tin can. Shooting the pink or black hog, which appear occasionally, reward players with a shotgun or machine gun for a temporary boost in fire power.